The present invention relates to novel processes for the production of 3,5-diamino-6-substituted-1,2,4-triazines in general, and the antiepileptic agent Lamotrigine in particular.
Lamotrigine 1, 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is an antiepileptic drug, and its analogues were first disclosed in British Patent No. 759,014 (1956). Subsequently, Lamotrigine and its analogues were described in Canadian Patent Nos. 1,112,643 and 1,133,938, and in U.S. Pat. No. 4,602,017. Processes for the preparation of Lamotrigine are also disclosed in international publications and patents WO 96/20934, WO 96/20935, WO 00/35888 and European Patent No. 963,980.
The process (as disclosed in Canadian Patent Nos. 1,112,643 and 1,133,938, U.S. Pat. No. 4,602,017 and in British Patent No. 759,014) for the preparation of Lamotrigine involves reaction of 2,3-dichlorobenzoyl cyanide 2 and aminoguanidine bicarbonate in dimethylsulfoxide and 8N aqueous nitric acid (scheme 1). The above process uses drastic conditions (20 eq. 8N HNO3), excess reagents and requires 7 days for completion of the reaction. The overall yield of the process from 2,3-dichlorobenzoyl cyanide is 15.6%. 
The process reported in WO 00/35888 for this reaction uses H2SO4 instead of 8N HNO3. However, it also suffers from lower yield (40%) and longer reaction time (2.5 days). The process also uses a large excess (xcx9c11 times) of sulfuric acid.
It is accordingly an object of the present invention to provide an improved process for the manufacture of lamotrigine which overcome the problems associated with poor efficiency described in the prior art. More broadly, it is an object of the present invention to provide novel processes for the production of 3,5-diamino-6-substituted-1,2,4-triazines.
In accordance with one aspect of the present invention, there is provided a process for the manufacture of an intermediate compound of formula IV 
useful for manufacturing 3,5-diamino-6-substituted-1,2,4-triazines, wherein R is an optionally substituted C1-C4 alkyl or aryl group, which process comprises reacting a compound of formula II: 
with aminoguanidine in the presence of an acid in an organic solvent under anhydrous conditions followed by treatment with a dehydrating reagent.
In accordance with another aspect of the present invention there is provided a process for the manufacture of 3,5-diamino-6-substituted-1,2,4-triazines of formula I: 
comprising the steps of:
(a) reacting a compound of formula (II): 
xe2x80x83with aminoguanidine salts, or equivalent thereof, in the presence of an acid in an organic solvent under anhydrous conditions to form a cyanohydrin of formula III: 
(b) dehydrating the cyanohydrin of formula III to form a compound of formula IV by treatment with a dehydrating reagent, 
xe2x80x83and
(c) cyclization of the compound of formula IV into a 3,5-diamino-6-substituted-1,2,4-triazine of compound of formula I or into a hydrated form thereof.
Suitably the substituted C1-C4 alkyl group is methyl, ethyl, propyl or butyl and the substituted aryl group is preferably 2,3-dichlorophenyl.
The process of the present invention provides a high yielding and cost-effective process for the preparation of 3,5-diamino-6-substituted-1,2,4-triazines in general and Lamotrigine in particular. This result is obtained through the use of an additive, namely a dehydrating agent, such as thionyl chloride, POCl3 or PCl5, and by employing organic acid in combination with a polar organic solvent, which stabilizes the cyanohydrin of formula III. The cyanohydrin of formula III upon addition of a dehydrating agent affords the intermediate iminoguanidine of formula IV (scheme 2).
The acid used in this process can be dry organosulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid, either in combination with dry polar organic solvents, such as dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP) or dimethylsulfoxide (DMSO), or combinations of a polar solvent with nonpolar solvents such as tetrahydrofuran (THF). The dehydrating reagents used in the process can be SOCl2, POCl3 or PCl5, oxalyl chloride, phosgene or equivalents thereof. 
The process, as shown in Scheme 2, involves the reaction of aryl cyanide, preferably 2,3-dichlorobenzoyl cyanide 2 (in which R=2,3-dichlorophenyl), with an organic acid, for example para-toluenesulfonic acid or methanesulfonic acid, and dry organic solvents, for example DMSO, NMP or DMF, at suitable temperatures to form an intermediate of formula III. The reaction mixture is treated with dehydrates for example SOCl2, POCl3 or PCl5, oxalyl chloride, phosgene or equivalent thereof at a suitable temperature to form the iminoguanidine of formula IV. The iminoguanidine salt in the reaction mixture is cyclized upon basification and heating. The iminoguanidine salt can be basified and isolated by filtration. The isolated iminoguanidine can be cyclized to form Lamotrigine using a base (such as NaOH, NH3 or KOH) in a protic solvent (such as methanol, ethanol, isopropanol or water). Lamotrigine 1 can be isolated as the monohydrate when the cyclization of the intermediate is carried out using base and isopropanol/water mixture or NMP/water. The lamotrigine monohydrate is a new compound and is further characterized in having the following peaks in powder X-ray diffraction pattern at an angle of two theta (2xcex8) is found to be: 10.34, 11.53, 12.46, 13.36, 13.86, 14.15, 14.94, 16.43, 16.65, 17.44, 17.97, 18.77, 18.91, 19.11, 19.52, 20.58, 22.11, 22.31, 23.09, 23.61, 24.18, 24.99, 25.52, 26.31, 26.83, 27.68, 28.53, 29.07, 29.24, 29.86, 30.09, 30.63, 31.01, 31.37, 31.78, 32.82, 33.25, 34.35, 34.96, 36.23, 36.92, 37.97, 38.60, 38.90. The positions of the peaks in powder X-ray diffraction pattern studies of anhydrous lamotrigine at an angle of two theta (2xcex8) to be 9.80, 11.39, 12,46, 13.29, 13.86, 14.13, 15.62, 16.66, 17.44, 17.97, 19.54, 20.56, 22.30, 22.89, 23.61, 24.81, 25.50, 26.31, 26.74, 27.87, 28.42, 28.86, 29.38, 29.66, 30.95, 31.66, 32.59, 33.23, 33.61, 33.83, 34.21, 35.20, 36.27, 37.16, 37.90, 38.35, 38.92, 39.17, 39.45.
The overall yield of lamotrigine is high (molar yield: 80xcx9c85%). The above described process is very cost-effective, operationally simple and completed in a short time period (6 to 10 hours).